IntroductionGastric cancer is the second most common cause of cancer-associated deaths worldwide [1]; therefore, early detectionand curative treatment are the best strategies to improve pa-tient survival. Detection of gastric cancers ≤20mm in diameteris particularly ideal because they are curable by minimally inva-sive treatment modalities, including endoscopic mucosal resec-tion and endoscopic submucosal dissection [2, 3]. Esophago-gastroduodenoscopy (EGD) is the most sensitive method forearly detection of gastric cancers, but it is often difficult whileusing conventional white-light imaging (C-WLI) endoscopy [4].Hence, new modalities are required.

In recent years, image-enhanced endoscopy (IEE), includingnarrow-band imaging (NBI) and blue-laser imaging (BLI), hasbeen used to improve visualization of microstructures and mi-crovessels in gastrointestinal lesions and to increase diagnosticaccuracy [5–7]. Previous studies have shown that conventionalIEE, including NBI and BLI, was effective for early detection ofneoplastic lesions in the esophagus and colon [8–10]. Al-though conventional IEE was also expected to facilitate earlydetection of gastric mucosal cancers, no studies have demon-strated its utility in this regard; this lack of evidence may be be-cause conventional IEE probably does not provide sufficientbrightness for effective examination of the stomach, whichhas a wider lumen compared with the esophagus and colon.

Linked color imaging improves the endoscopic visibility of gastricmucosal cancers

Authors

Yoshiyasu Kitagawa1, Takuto Suzuki1, Taro Hara2, Rino Nankinzan1, Hideyuki Takashiro1, Osamu Sugita1, Hiroshi

Imazeki3, Taketo Yamaguchi3

Institutions

1 Endoscopy Division, Chiba Cancer Center, Chiba, Japan

2 Hara Clinic, Chiba, Japan

3 Department of Gastroenterology, Chiba Cancer Center,

Chiba, Japan

submitted 25.1.2018

accepted after revision 11.6.2018

Bibliography

DOI https://doi.org/10.1055/a-0733-7086 |

Endoscopy International Open 2019; 07: E164–E170

© Georg Thieme Verlag KG Stuttgart · New York

ISSN 2364-3722

Corresponding author

Yoshiyasu Kitagawa, MD, Endoscopy Division, Chiba Cancer

Center, 666-2 Nitonacho, Chuo-ku, Chiba, Japan

Fax: +043-262-8680

ykitagawa@chiba-cc.jp

ABSTRACT

Background and study aims As a newly developed

endoscopy technique, linked color imaging (LCI) provides

very bright images with enhanced color tones. With the ob-

jective of improving the detection rate of gastric mucosal

cancers, which are often difficult to detect, we examined

the utility of LCI from the viewpoint of visibility.

Patients and methods The current study used 100 conse-

cutive gastric mucosal cancers ≤20mm in diameter. For

each lesion, we selected one endoscopic image acquired

by white-light imaging (WLI), blue-laser imaging (BLI)

-bright, and LCI modes. Four endoscopists interpreted the

images; using a previously reported scale, we scored the

visibility level on a scale of 1–4.

Results The mean (± SD) visibility scores were 2.54±1.10

for WLI, 3.02±1.07 for BLI-bright, and 3.28±0.97 for LCI.

The score was significantly higher for BLI-bright compared

with WLI (P< .001) and again higher for LCI compared with

BLI-bright (P < .001). For the experts, the scores for BLI-

bright and LCI were similar, but both were significantly

higher than the score for WLI. For the trainees, there was

no significant difference between the WLI and BLI-bright

scores, but LCI score was significantly higher than those for

WLI and BLI-bright scores. With regard to clinical character-

istics, LCI particularly enhanced visibility of normochromic,

flat and depressed lesions, which had the lowest visibility

scores of all three modalities compared with those of the

other lesions.

Conclusion LCI increased visibility and may contribute to

early detection of gastric mucosal cancers.

Original article

E164 Kitagawa Yoshiyasu et al. Linked color imaging… Endoscopy International Open 2019; 07: E164–E170

Published online: 2019-01-18

Linked color imaging (LCI) (Fujifilm Co., Tokyo, Japan) is anewly developed IEE modality that provides images with en-hanced brightness and visualization of red lesions and whitishlesions during routine endoscopy. Another merit is that LCI ima-ges resemble color-enhanced C-WLI images; thus, eliminatingthe need for special training. We reported that LCI increases vis-ibility of flat colorectal lesions [11]. Previous studies, whichwere case series involving a small number of patients, reportedthat LCI enhances early gastric cancer lesions [12, 13]. However,the efficacy of this modality compared with conventional IEEremains unknown.

With the aim of examining the utility of LCI in improving de-tection of gastric mucosal cancer, we conducted a retrospectivestudy to compare three modalities, including WLI, BLI-bright,and LCI, with regard to their ability to facilitate the visualizationof gastric mucosal cancer.

Patients and methodsBetween December 2014 and July 2017, 113 consecutive earlygastric cancers were examined by EGD and were histologicallyproven mucosal cancers that measured≤20mm in diameter atChiba Cancer Center, Chiba, Japan. One expert (Y. K.) took allthe endoscopic images. Thirteen cases examined using a NBIsystem (Olympus Medical Systems, Tokyo, Japan) were exclud-ed from the analysis. Thus, the current study used endoscopicimages of 100 early gastric cancers, examined using a LASEREOsystem (FUJIFILM, Tokyo, Japan) with an EG-L590ZW or L600ZW

endoscope. For all lesions, we selected one image each ac-quired by WLI, BLI-bright, and LCI from the same site or fromthe intermediate or distant view. A total of 100 images wereprepared for each modality.

Before the study, surface colors in WLI were evaluated bytwo experts (Y. K. and T.H.) and then divided into three groups;whitish, normochromic, and reddish lesions. They were diag-nosed based on the predominant color. The endoscopic imagesof WLI, BLI-bright, and LCI were randomly displayed and inde-pendently reviewed by four endoscopists, including two ex-perts and two trainees, in a single session without prior knowl-edge of the lesions. In this study, the endoscopists were definedas experts when their experience in using IEE was over 5 years oras trainees when their experience was less than 1 year. Imageswere electronically presented without zooming; image size waspredetermined and similar to that used during routine endo-scopic monitoring. The reviewers did not refer to earlier ima-ges. They scored the lesions based on a previously reported 4-point visibility scale [11, 14], as follows: score 4, excellent (easi-ly detectable); score 3, good (detectable with careful observa-tion); score 2, fair (hardly detectable without careful examina-tion); and score 1, poor (not detectable without repeated care-ful examination). Previous study demonstrated that this scorewas related to an objective indicator such as color differencevalue [15]. A representative image for each score is shown in

▶Fig. 1.The current study was approved by the ethics committee of

Chiba Cancer Center and the contents were displayed on the

▶ Fig. 1 Representative lesions with visibility scores 1–4 using the three modalities. WLI, white-light imaging; BLI-bright, blue-laser imaging-bright; LCI, linked color imaging.

Kitagawa Yoshiyasu et al. Linked color imaging… Endoscopy International Open 2019; 07: E164–E170 E165

notice board for inpatients and outpatients. The study was car-ried out in accordance with the World Medical Association’sDeclaration of Helsinki, and all the patients provided informedconsent for undergoing EGD.

Histopathologic diagnosis

Lesion specimens were obtained by endoscopic resection andwere fixed with 10% formalin. Histopathological diagnosis wasperformed according to the Japanese Classification of GastricCarcinoma [16].

LCI, the novel image-enhancing mode

We used an endoscopic system employing a laser light source(LASEREO), which has two lasers with different wavelengths;white-light laser (wavelength 450±10nm) provides a widespectrum of white light illumination, suitable for general obser-vation, whereas BLI mode laser comprises short wavelength(410±10nm) and narrow band. BLI mode provides high con-trast signals to obtain information regarding capillaries on themucosal surface, slight mucosal irregularities, and deep bloodvessels. The intermediate mode BLI-bright, which has a higherwhite light intensity ratio, provides a brighter image. LCI usedin the current study was a novel image-enhanced mode basedon BLI-bright imaging with additional processing that en-hanced red color separation to depict red and white colorsmore vividly. Because LCI enhanced color contrast, color differ-ence between the surrounding tissue and lesions, includinglight-colored lesions, is emphasized, thereby facilitating visuali-zation.

Statistical analysis

Clinical data were expressed as percentage, mean, and range.The mean (± SD) of the visibility scores was calculated. Meanscores of all endoscopists, the expert group, and the traineegroup were analyzed and compared among the modalitiesusing paired t-test. The modalities were also compared in termsof various clinical characteristics, including surface color andmacroscopic type. P values < 0.05 were considered to be signif-icant. Statistical analyses were performed using SPSS software,version 17.0 (SPSS Inc, Chicago, IL).

Results

Patient characteristics are summarized in ▶Table1. Median pa-tient age was 74.5 (62–90) years, with a preponderance of men(n=77). Median lesion size was 10mm (2–20mm), and surfacecolors were whitish in 16, normochromic in 55, and reddish in29 lesions. Macroscopic types were as follows: protruding in33, flat in 14, and depressed in 53.Gastric lesions were locatedin the upper third in 17 patients, in the middle third in 16 pa-tients, and in the lower third in 67 patients. There were 94cases of well-differentiated tubular adenocarcinoma and sixcases of moderately differentiated tubular adenocarcinoma.Representative cases are shown in ▶Fig. 2, ▶Fig. 3, ▶Fig. 4,and ▶Fig. 5.

Mean (± SD) visibility scores of the four endoscopists were2.54±1.10 for WLI, 3.02±1.07 for BLI-bright, and 3.28±0.97for LCI. The score for BLI-bright was significantly higher than

that for WLI (P<0.001) and the score for LCI (P<0.001) was sig-nificantly higher than that for BLI-bright mode. For the experts,the score for BLI-bright was significantly higher than that forWLI (3.23±0.95 vs. 2.51±1.08; P<0.001), but there was no dif-ference between the scores for BLI-bright and LCI (3.23±0.95vs. 3.38±0.83). For the trainees, there was no difference be-tween the scores for WLI (2.57±1.12) and BLI-bright (2.79±1.13), but the score for LCI (3.18±1.08) was significantly higherthan that for WLI and BLI-bright (P<0.001) (▶Table 2).

Distribution of scores for the three modalities is shown in

▶Fig. 6. The proportion of cases with scores 3 and 4, which re-presented good visibility, was 50.3% for WLI compared with79 % for LCI. Conversely, the proportion of cases with scores 1and 2, which represented poor visibility, was 49.8% for WLIcompared with 21% for LCI. Next, when the mean score of thefour endoscopists was calculated for each lesion, 28 cases hadmean scores of 2 or lower on WLI, 15 (53.6%) of which hadscores of 3 or higher on LCI. Among 13 cases with scores of 2or lower on BLI-bright, 3 cases (23.1%) showed scores of 3 orhigher on LCI. Based on the assessment of four endoscopists,two lesions had mean scores of 2 or lower on LCI, but neitherof the two showed scores of 3 or higher on WLI or BLI-bright.

Mean visibility scores of the four endoscopists, in terms ofvarious clinical characteristics including surface color and mac-roscopic type, are shown in ▶Table3. With regard to surface

▶ Table 1 Baseline clinicopathologic characteristics.

No. of patients 100

Male/female, no. 77/23

Median age (range), years 74.5 (62– 90)

Lesion size, median (range), mm 10.0 (2–20)

Surface color

▪ Whitish 16

▪ Normochromic 55

▪ Reddish 29

Macroscopic type

▪ Elevated 33

▪ Flat 14

▪ Depressed 53

Location of the gastric lesion

▪ Upper third 17

▪ Middle third 16

▪ Lower third 67

Histology

▪ Tub1 94

▪ Tub2 6

Tub1, well-differentiated tubular adenocarcinoma; Tub2, moderately differ-entiated tubular adenocarcinoma.

E166 Kitagawa Yoshiyasu et al. Linked color imaging… Endoscopy International Open 2019; 07: E164–E170

Original article

color, mean (± SD) visibility scores for WLI, BLI-bright, and LCI innormochromic lesions were 2.15±1.03, 2.78±1.10, and 3.08±1.04, respectively, which were lower those for whitish lesions(3.14±1.10, 3.47±0.93, and 3.69±0.64, respectively) and red-dish lesions (2.95±0.91, 3.23±0.97, and 3.42±0.88, respec-

tively). These findings indicated that in normochromic lesions,although visibility scores for all three modalities were lowerthan those in whitish and reddish lesions, the score for LCI re-mained significantly higher than those for the other two mod-alities. With regard to macroscopic type, mean (± SD) visibility

▶ Fig. 2 a White-light imaging shows a whitish lesion (arrow) in the lower third of the stomach: mean visibility score, 3.75. b Blue-laser ima-ging-bright: mean visibility score, 3.50. c Linked color imaging enables enhanced visualization of the whitish lesion: mean visibility score,4.00.

▶ Fig. 3 a White-light imaging shows a reddish lesion (arrow) in the lower third of the stomach: mean visibility score, 3.50. b Blue-laser ima-ging-bright: mean visibility score, 3.75. c Linked color imaging enables enhanced visualization of the reddish lesion: mean visibility score,4.00.

▶ Fig. 4 Endoscopic images of the same gastric mucosal cancer (case #1). a White-light imaging shows a depressed lesion (arrow) in theupper third of the stomach: mean visibility score, 1.75. b Blue-laser imaging-bright: mean visibility score, 2.75. c Linked color imaging, whichprovides a high color contrast image to vividly differentiate between the cancerous lesion and the surrounding normal mucosa: mean visibilityscore, 3.50.

Kitagawa Yoshiyasu et al. Linked color imaging… Endoscopy International Open 2019; 07: E164–E170 E167

scores in flat and depressed lesions were 2.33±1.04 for WLI,2.84±1.09 for BLI-bright, and 3.15±1.02 for LCI, which werelower than the scores in protruding lesions (2.95±1.11, 3.39±0.93, and 3.53±0.80, respectively). These findings showed thatin flat and depressed lesions, although visibility scores of allthree modalities were lower than those in protruding lesions,the score for LCI remained significantly higher than those forthe other two modalities.

DiscussionIn the current study, we proved that, compared with WLI andBLI-bright modes, LCI mode improved visibility of gastric muco-sal cancers measuring≤20mm in diameter. Upon comparingvisibility scores of experts with those of trainees, those for BLI-bright and LCI were significantly higher than those for WLI, withno significant difference between the scores for BLI-bright andLCI in experts; conversely, in trainees, the score for LCI was sig-nificantly higher than the scores for WLI and BLI-bright, with nosignificant difference between WLI and BLI-bright. One possiblereason for these results was that the images of conventionalIEE, such as BLI-bright, had completely different color tonescompared with those of standard WLI and that some familiari-zation was required. In contrast, because LCI images resembledcolor-enhanced WLI images, LCI may have a steep learningcurve and is easy to adopt even in facilities with limited oppor-tunities to diagnose early gastric cancer. Therefore, this modal-ity could be extremely useful in actual clinical practice, may en-able IEE for observation, and can potentially become the stand-ard method for detection of gastric cancer.

In this study, distribution of surface colors was similar to thatreported in a previous study [17]. With regard to surface color,the score for LCI in normochromic lesions was significantlyhigher than those for WLI and BLI-bright. This is because LCI en-hances color separation and depicts red lesions even redderand white lesions whiter, which contributes to demonstratinglarge color differences in color contrast between a malignantlesion and the surrounding area, even if poor tone difference is

▶ Fig. 5 Endoscopic images of the same gastric mucosal cancer (case #2). a White-light imaging shows a flat lesion (arrow) in the lower thirdof the stomach: mean visibility score, 2.25. b Blue-laser imaging-bright: mean visibility score, 2.75. c Linked color imaging, which enhancesmucosal irregularity: mean visibility score, 3.00.

▶ Table 2 Mean visibility scores of endoscopists (experts and trainees) for WLI, BLI-bright, and LCI modalities.

Endoscopist WLI BLI-bright LCI WLI vs. BLI-bright,

P value

WLI vs. LCI,

P value

BLI-bright vs. LCI,

P value

All, mean ± SD 2.54 ±1.10 3.02±1.07 3.28±0.97 <0.001 < 0.001 <0.001

Expert, mean± SD 2.51 ±1.08 3.23±0.95 3.38±0.83 <0.001 < 0.001 NS

Trainee, mean± SD 2.57 ±1.12 2.79±1.13 3.18±1.08 NS < 0.001 <0.001

WLI, white-light imaging; BLI, blue-laser imaging; LCI, linked color imaging; SD, standard deviation; NS, not significant.

WLI

BLI-bright

LCI

88 111 98 103

57 53 114 176

31 53 89 227

0

Visibility score 1 2 3 4

50 100 150 200

Numbers

250 300 350 400

▶ Fig. 6 Distribution of visibility scores. For each modality, thetotal scores of all endoscopists were counted. WLI, white-lightimaging; BLI-bright, blue-laser imaging-bright; LCI, linked colorimaging.

E168 Kitagawa Yoshiyasu et al. Linked color imaging… Endoscopy International Open 2019; 07: E164–E170

Original article

visualized in the other two modalities. In contrast, scores for LCIin whitish and reddish lesions were not significantly higher thanthose for BLI-bright. This result may be explained by the ima-ging principle of BLI-bright, which involves use of light that iseasily absorbed by the hemoglobin in capillaries, thereby clear-ly delineating blood vessels in the reddish lesions as brownish incolor. In addition, when a whitish lesion is present, red bloodvessels in the surrounding area are also amplified. Interruptionof the underlying mucosal vascular pattern provides an indirectfinding to facilitate lesion recognition.

In our study, we found that LCI was effective in enhancingflat and depressed lesions, which may not be visible on WLI be-cause of their subtle appearance and the limited contrast of thesurrounding mucosa [18, 19]. Previous case studies also report-ed that LCI enhanced early gastric cancer lesions in patientswith these clinical features [12, 13]. Although BLI-bright pro-vides brighter endoscopic views, the imaging is still criticizedfor darkness when used in the stomach [20]. Therefore, BLI-bright probably does not contribute to detection of subtlechanges in early gastric cancer. In contrast, LCI used in the cur-rent study yielded very bright images and enhanced mucosal ir-regularities, even in the middle to distant views, and enabledidentification of abnormal lesions. The previous study usingsame visibility scores also showed that LCI improved endo-scopic visibility of colorectal flat lesions [11]. Thus, the poten-tial benefit of LCI in detecting flat and depressed lesions mayhave clinical implications, especially in screening for early gas-tric cancers.

Early gastric cancer is often overlooked during ordinaryendoscopy because it is more difficult to detect than mostother upper gastrointestinal tract cancers [4]. The reportedrate of missing superficial gastric cancers is 4.6% to 25.8%[21–23]. Failure to detect early gastric cancer during endos-copy may contribute to poor prognosis [21]. Thus, a variety ofpremedication and screening techniques are available to en-sure the quality of EGD [24, 25]. When the distribution of scoreswas analyzed in our study, the rate of poor visibility of LCI modewas lower than that of WLI. With regard to the mean score ofthe four endoscopists for each lesion, over half of the casesthat had poor visibility scores on WLI showed good visibility

scores on LCI. We supposed that LCI was advantageous in im-proving diagnosis of subtle, early gastric cancer.

Recently, some studies concerning efficacy of LCI for earlygastric cancer have been reported [26, 27]. One report showedobjective data on color change, but this study can demonstrateonly improved visibility by color deference of each modality[24]. Another report used scores for improvements, which can-not evaluate visibility of baseline modality [25]. Thus, addition-al reports are required to build consensus about usefulness ofLCI, which is a newly developed IEE modality. The strong pointof this study is evaluation of each modality including WLI ima-ges, which are the basis of comparison. In addition, this studyused the visibility scale, which has been used in several reportsof IEE. Although this report used the subjective indicator, theresult clearly showed a sufficient improvement of LCI for earlygastric cancer.

The current study had some limitations. In this study, stillimages and not videos were reviewed, and the possibility of se-lection bias persists. The method of consecutive reviews of thesame image in different modalities during a single sessioncould have led to another bias. Because this study includedonly gastric mucosal cancers, further studies are required toclarify whether LCI is superior to WLI in differentiating betweenmalignant and nonmalignant lesions. Furthermore, this was asingle-center retrospective study; a multicenter prospectivestudy may be more accurate in assessing the effectiveness ofthis new modality for early detection of gastric cancers. None-theless, the current study did provide evidence based on a rela-tively large number of cases that LCI significantly improved vis-ibility compared with the other modalities under the same con-ditions.

ConclusionIn conclusion, LCI enhanced the visibility of early gastric cancerand may contribute to the early detection of these lesions. Fu-ture application of LCI in gastric screening is anticipated.

▶ Table 3 Mean visibility scores of endoscopists, in terms of various clinical characteristics.

WLI BLI-bright LCI WLI vs. BLI-bright,

P value

WLI vs. LCI,

P value

BLI-bright vs. LCI,

P value

Surface color

▪ Whitish 3.14±1.10 3.47±0.93 3.69± 0.64 NS <0.001 NS

▪ Normochromic 2.15±1.03 2.78±1.10 3.08± 1.04 <0.001 <0.001 <0.001

▪ Reddish 2.95±0.91 3.23±0.97 3.42± 0.88 <0.001 <0.001 NS

Macroscopic type

▪ Protruding 2.95±1.11 3.39±0.93 3.53± 0.80 <0.001 <0.001 NS

▪ Flat and depressed 2.33±1.04 2.84±1.09 3.15± 1.02 <0.001 <0.001 <0.001

WLI, white-light imaging; BLI, blue-laser imaging; LCI, linked color imaging; SD, standard deviation; NS, not significant.

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Competing interests

None

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Original article